Abstract:
Lynch syndrome (LS) is an inherited cancer predisposition disorder associated with an elevated risk of developing various solid cancers, but mostly colorectal cancer (CRC). Despite having the same germline pathogenic variant (PV) in one of the mis-match repair genes or the EPCAM gene, Lynch syndrome variant heterozygotes (LSVH) exhibit a remarkable phenotypic variability in the risk of developing cancer. The role of human leukocyte antigen (HLA) in modifying cancer development risk prompted our hypothesis into whether HLA variations act as potential genetic modifiers influencing the age at cancer diagnosis in LSVH. To investigate this, we studied a unique cohort of 426 LSVH carrying the same germline PV in the hMLH1 gene (MLH1:c.1528C > T) in South Africa. We intuitively selected 100 LSVH with the greatest diversity in age at cancer diagnosis (N = 80) and the oldest cancer unaffected LSVH (N = 20) for a high-throughput HLA genotyping of 11 HLA class I and class II loci using the shotgun next-generation sequencing (NGS) technique on the Illumina MiSeq platform. Statistical analyses employed Kaplan-Meier survival analyses with log-rank tests, and Cox proportional hazards using binned HLA data to minimize type I error. Significant associations were observed between young age at cancer diagnosis and HLA-DPB1*04:02 (mean age: 37 y (25-50); hazard ratio (HR) = 3.37; corrected p-value (q) = 0.043) as well as HLA-DPB1 binned alleles (including HLA-DPB1*09:01, HLA-DPB1*10:01, HLA-DPB1*106:01, HLA-DPB1*18:01, HLA-DPB1*20:01, HLA-DPB1*26:01, HLA-DPB1*28:01, HLA-DPB1*296:01, and HLA-DPB1*55:01) (mean age: 37 y (17-63); HR = 2.30, q = 0.045). The involvement of HLA-DPB1 alleles in the age at cancer diagnosis may highlight the potential role of HLA class II in the immune response against cancer development in LSVH. When validated in a larger cohort, these high-risk HLA-DPB1 alleles could be factored into cancer risk prediction models for personalized cancer screening in LSVH.
摘要:
Lynch综合征(LS)是一种遗传性癌症易感性疾病,与发展各种实体癌的风险升高有关,但主要是结直肠癌(CRC)。尽管在一个错配修复基因或EPCAM基因中具有相同的种系致病变体(PV),Lynch综合征变异杂合子(LSVH)在患癌症的风险中表现出明显的表型变异性。人类白细胞抗原(HLA)在改变癌症发展风险中的作用促使我们假设HLA变异是否作为影响LSVH癌症诊断年龄的潜在遗传修饰因子。为了调查这一点,我们在南非研究了426个携带相同种系PV的LSVH的独特队列hMLH1基因(MLH1:c.1528C>T).我们在IlluminaMiSeq平台上使用shot弹枪下一代测序(NGS)技术,直观地选择了100个癌症诊断年龄最大的LSVH(N=80)和最古老的未受影响的LSVH(N=20),用于11个HLAI类和II类基因座的高通量HLA基因分型。统计分析采用Kaplan-Meier生存分析和对数秩检验,和Cox比例风险使用分类的HLA数据来最小化I型错误。在癌症诊断的年轻年龄与HLA-DPB1*04:02(平均年龄:37y(25-50);危险比(HR)=3.37;校正p值(q)=0.043)以及HLA-DPB1合并等位基因(包括HLA-DPB1*09:01,HLA-DPB1*10:01,HLA-DPB1*10:01,HLA-DP37:01B1*HLA:01=平均HLA-DPB1等位基因在癌症诊断年龄中的参与可能突出了HLAII类在LSVH中针对癌症发展的免疫反应中的潜在作用。当在更大的队列中验证时,这些高危HLA-DPB1等位基因可纳入癌症风险预测模型,用于LSVH个性化癌症筛查.